Evaluation of plasma tau and neurofilament light chain biomarkers in a 12-year clinical cohort of human prion diseases.
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
received:
27
07
2020
accepted:
02
02
2021
revised:
20
01
2021
pubmed:
7
3
2021
medline:
3
2
2022
entrez:
6
3
2021
Statut:
ppublish
Résumé
Prion diseases are fatal neurodegenerative conditions with highly accurate CSF and imaging diagnostic tests, but major unmet needs for blood biomarkers. Using ultrasensitive immuno-assays, we measured tau and neurofilament light chain (NfL) protein concentrations in 709 plasma samples taken from 377 individuals with prion disease during a 12 year prospective clinical study, alongside healthy and neurological control groups. This provides an unprecedented opportunity to evaluate their potential as biomarkers. Plasma tau and NfL were increased across all prion disease types. For distinguishing sCJD from control groups including clinically-relevant "CJD mimics", both show considerable diagnostic value. In sCJD, NfL was substantially elevated in every sample tested, including during early disease with minimal functional impairment and in all follow-up samples. Plasma tau was independently associated with rate of clinical progression in sCJD, while plasma NfL showed independent association with severity of functional impairment. In asymptomatic PRNP mutation carriers, plasma NfL was higher on average in samples taken within 2 years of symptom onset than in samples taken earlier. We present biomarker trajectories for nine mutation carriers healthy at enrolment who developed symptoms during follow-up. NfL started to rise as early as 2 years before onset in those with mutations typically associated with more slowly progressive clinical disease. This shows potential for plasma NfL as a "proximity marker", but further work is needed to establish predictive value on an individual basis, and how this varies across different PRNP mutations. We conclude that plasma tau and NfL have potential to fill key unmet needs for biomarkers in prion disease: as a secondary outcome for clinical trials (NfL and tau); for predicting onset in at-risk individuals (NfL); and as an accessible test for earlier identification of patients that may have CJD and require more definitive tests (NfL). Further studies should evaluate their performance directly in these specific roles.
Identifiants
pubmed: 33674752
doi: 10.1038/s41380-021-01045-w
pii: 10.1038/s41380-021-01045-w
pmc: PMC8758487
mid: EMS115797
doi:
Substances chimiques
Biomarkers
0
Neurofilament Proteins
0
tau Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5955-5966Subventions
Organisme : European Research Council
ID : 681712
Pays : International
Organisme : Medical Research Council
ID : MC_U123170362
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00024/6
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0400713
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_U123160655
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00024/9
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00024/1
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00024/5
Pays : United Kingdom
Informations de copyright
© 2021. The Author(s).
Références
Surveillance Data from the UK. https://www.cjd.ed.ac.uk/sites/default/files/figs.pdf , 2018, Accessed Date Accessed 2018 Accessed.
Collinge J, Clarke AR. A general model of prion strains and their pathogenicity. Science. 2007;318:930–6.
doi: 10.1126/science.1138718
Puoti G, Bizzi A, Forloni G, Safar JG, Tagliavini F, Gambetti P. Sporadic human prion diseases: molecular insights and diagnosis. Lancet Neurol. 2012;11:618–28.
doi: 10.1016/S1474-4422(12)70063-7
Bongianni M, Orru C, Groveman BR, Sacchetto L, Fiorini M, Tonoli G, et al. Diagnosis of Human Prion Disease Using Real-Time Quaking-Induced Conversion Testing of Olfactory Mucosa and Cerebrospinal Fluid Samples. JAMA Neurol. 2017;74:155–62.
doi: 10.1001/jamaneurol.2016.4614
Rudge P, Hyare H, Green A, Collinge J, Mead S. Imaging and CSF analyses effectively distinguish CJD from its mimics. J Neurol Neurosurg Psychiatry. 2018;89:461–6.
doi: 10.1136/jnnp-2017-316853
White AR, Enever P, Tayebi M, Mushens R, Linehan J, Brandner S, et al. Monoclonal antibodies inhibit prion replication and delay the development of prion disease. Nature. 2003;422:80–83.
doi: 10.1038/nature01457
Collinge J, Gorham M, Hudson F, Kennedy A, Keogh G, Pal S, et al. Safety and efficacy of quinacrine in human prion disease (PRION-1 study): a patient-preference trial. Lancet Neurol. 2009;8:334–44.
doi: 10.1016/S1474-4422(09)70049-3
Varges D, Manthey H, Heinemann U, Ponto C, Schmitz M, Schulz-Schaeffer WJ, et al. Doxycycline in early CJD: a double-blinded randomised phase II and observational study. J Neurol Neurosurg Psychiatry. 2017;88:119–25.
doi: 10.1136/jnnp-2016-313541
Geschwind MD, Kuo AL, Wong KS, Haman A, Devereux G, Raudabaugh BJ, et al. Quinacrine treatment trial for sporadic Creutzfeldt-Jakob disease. Neurology. 2013;81:2015–23.
doi: 10.1212/WNL.0b013e3182a9f3b4
Haik S, Marcon G, Mallet A, Tettamanti M, Welaratne A, Giaccone G, et al. Doxycycline in Creutzfeldt-Jakob disease: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2014;13:150–8.
doi: 10.1016/S1474-4422(13)70307-7
Raymond GJ, Zhao HT, Race B, Raymond LD, Williams K, Swayze EE, et al. Antisense oligonucleotides extend survival of prion-infected mice. JCI Insight. 2019;5:e131175.
doi: 10.1172/jci.insight.131175
Sixth UCLH patient to receive innovative drug for CJD. https://www.uclh.nhs.uk/News/Pages/SixthUCLHpatienttoreceiveinnovativedrugforCJD.aspx , 2019, Accessed Date Accessed 2019 Accessed.
Mead S, Burnell M, Lowe J, Thompson A, Lukic A, Porter MC, et al. Clinical Trial Simulations Based on Genetic Stratification and the Natural History of a Functional Outcome Measure in Creutzfeldt-Jakob Disease. JAMA Neurol. 2016;73:447–55.
doi: 10.1001/jamaneurol.2015.4885
Minikel EV, Vallabh SM, Orseth MC, Brandel JP, Haik S, Laplanche JL, et al. Age at onset in genetic prion disease and the design of preventive clinical trials. Neurology. 2019;93:e125–e134.
doi: 10.1212/WNL.0000000000007745
Gaetani L, Blennow K, Calabresi P, Di Filippo M, Parnetti L, Zetterberg H. Neurofilament light chain as a biomarker in neurological disorders. J Neurol Neurosurg Psychiatry. 2019;90:870–81.
doi: 10.1136/jnnp-2018-320106
Steinacker P, Feneberg E, Weishaupt J, Brettschneider J, Tumani H, Andersen PM, et al. Neurofilaments in the diagnosis of motoneuron diseases: a prospective study on 455 patients. J Neurol Neurosurg Psychiatry. 2016;87:12–20.
pubmed: 26296871
Kovacs GG, Andreasson U, Liman V, Regelsberger G, Lutz MI, Danics K, et al. Plasma and cerebrospinal fluid tau and neurofilament concentrations in rapidly progressive neurological syndromes: a neuropathology-based cohort. Eur J Neurol. 2017;24:1326–e1377.
doi: 10.1111/ene.13389
Thompson AGB, Luk C, Heslegrave AJ, Zetterberg H, Mead SH, Collinge J, et al. Neurofilament light chain and tau concentrations are markedly increased in the serum of patients with sporadic Creutzfeldt-Jakob disease, and tau correlates with rate of disease progression. J Neurol Neurosurg Psychiatry. 2018;89:955–61.
doi: 10.1136/jnnp-2017-317793
Piehl F, Kockum I, Khademi M, Blennow K, Lycke J, Zetterberg H, et al. Plasma neurofilament light chain levels in patients with MS switching from injectable therapies to fingolimod. Mult Scler. 2018;24:1046–54.
doi: 10.1177/1352458517715132
Preische O, Schultz SA, Apel A, Kuhle J, Kaeser SA, Barro C, et al. Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease. Nat Med. 2019;25:277–83.
doi: 10.1038/s41591-018-0304-3
Byrne LM, Rodrigues FB, Blennow K, Durr A, Leavitt BR, Roos RAC, et al. Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington’s disease: a retrospective cohort analysis. Lancet Neurol. 2017;16:601–9.
doi: 10.1016/S1474-4422(17)30124-2
Thompson AG, Lowe J, Fox Z, Lukic A, Porter MC, Ford L, et al. The Medical Research Council prion disease rating scale: a new outcome measure for prion disease therapeutic trials developed and validated using systematic observational studies. Brain. 2013;136:1116–27.
doi: 10.1093/brain/awt048
Zerr I, Kallenberg K, Summers DM, Romero C, Taratuto A, Heinemann U, et al. Updated clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease. Brain. 2009;132:2659–68.
doi: 10.1093/brain/awp191
Fluss R, Faraggi D, Reiser B. Estimation of the Youden Index and its associated cutoff point. Biom J. 2005;47:458–72.
doi: 10.1002/bimj.200410135
Wadsworth JDF, Adamson G, Joiner S, Brock L, Powell C, Linehan JM, et al. Methods for Molecular Diagnosis of Human Prion Disease. Methods Mol Biol. 2017;1658:311–46.
doi: 10.1007/978-1-4939-7244-9_22
Hill AF, Joiner S, Wadsworth JD, Sidle KC, Bell JE, Budka H, et al. Molecular classification of sporadic Creutzfeldt-Jakob disease. Brain. 2003;126:1333–46.
doi: 10.1093/brain/awg125
Parchi P, de Boni L, Saverioni D, Cohen ML, Ferrer I, Gambetti P, et al. Consensus classification of human prion disease histotypes allows reliable identification of molecular subtypes: an inter-rater study among surveillance centres in Europe and USA. Acta Neuropathol. 2012;124:517–29.
doi: 10.1007/s00401-012-1002-8
Mead S, Lloyd S, Collinge J. Genetic Factors in Mammalian Prion Diseases. Annu Rev Genet. 2019;53:117–47.
doi: 10.1146/annurev-genet-120213-092352
Zanusso G, Monaco S, Pocchiari M, Caughey B. Advanced tests for early and accurate diagnosis of Creutzfeldt-Jakob disease. Nat Rev Neurol. 2016;12:427.
doi: 10.1038/nrneurol.2016.92
Hepner A, Porter J, Hare F, Nasir SS, Zetterberg H, Blennow K, et al. Serum Neurofilament Light, Glial Fibrillary Acidic Protein and Tau Are Possible Serum Biomarkers for Activity of Brain Metastases and Gliomas. World J Oncol. 2019;10:169–75.
doi: 10.14740/wjon1228
Minikel EV, Zhao HT, Le J, O’Moore J, Pitstick R, Graffam S, et al. Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints. Nucleic Acids Res. 2020;48:10615–31.
doi: 10.1093/nar/gkaa616
Steinacker P, Blennow K, Halbgebauer S, Shi S, Ruf V, Oeckl P, et al. Neurofilaments in blood and CSF for diagnosis and prediction of onset in Creutzfeldt-Jakob disease. Sci Rep. 2016;6:38737.
doi: 10.1038/srep38737
Staffaroni AM, Kramer AO, Casey M, Kang H, Rojas JC, Orru CD, et al. Association of Blood and Cerebrospinal Fluid Tau Level and Other Biomarkers With Survival Time in Sporadic Creutzfeldt-Jakob Disease. JAMA Neurol. 2019;76:969–77.
doi: 10.1001/jamaneurol.2019.1071
Abu-Rumeileh. Comparison between plasma and cerebrospinal fluid biomarkers for the early diagnosis and association with survival in prion disease. J Neurol Neurosurg Psychiatry. 2020;91:1181–8.
Vallabh SM, Minikel EV, Schreiber SL, Lander ES. Towards a treatment for genetic prion disease: trials and biomarkers. Lancet Neurol. 2020;19:361–8.
doi: 10.1016/S1474-4422(19)30403-X
Vallabh SM, Minikel EV, Williams VJ, Carlyle BC, McManus AJ, Wennick CD, et al. Cerebrospinal fluid and plasma biomarkers in individuals at risk for genetic prion disease. BMC Med. 2020;18:140.
doi: 10.1186/s12916-020-01608-8